The Cognitive Role of the Globus Pallidus interna; Insights from Disease States.

The motor symptoms of both Parkinson's disease and focal dystonia arise from dysfunction of the basal ganglia, and are improved by pallidotomy or deep brain stimulation of the Globus Pallidus interna (GPi). However, Parkinson's disease is associated with a greater degree of basal ganglia-dependent learning impairment than dystonia. We attempt to understand this observation in terms of a comparison of the electrophysiology of the output of the basal ganglia between the two conditions. We use the natural experiment offered by Deep Brain Stimulation to compare GPi local field potential responses in subjects with Parkinson's disease compared to subjects with dystonia performing a forced-choice decision-making task with sensory feedback. In dystonic subjects, we found that auditory feedback was associated with the presence of high gamma oscillations nestled on a negative deflection, morphologically similar to sharp wave ripple complexes described in human rhinal cortex. These were not present in Parkinson's disease subjects. The temporal properties of the high gamma burst were modified by incorrect trial performance compared to correct trial performance. Both groups exhibited a robust low frequency response to 'incorrect' trial performance in dominant GPi but not non-dominant GPi at theta frequency. Our results suggest that cellular processes associated with striatum-dependent memory function may be selectively impaired in Parkinson's disease even if dopaminergic drugs are administered, but that error detection mechanisms are preserved.

Unbalanced Peptidergic Inhibition in Superficial Neocortex Underlies Spike and Wave Seizure Activity.

Slow spike and wave discharges (0.5-4 Hz) are a feature of many epilepsies. They are linked to pathology of the thalamocortical axis and a thalamic mechanism has been elegantly described. Here we present evidence for a separate generator in local circuits of associational areas of neocortex manifest from a background, sleep-associated delta rhythm in rat. Loss of tonic neuromodulatory excitation, mediated by nicotinic acetylcholine or serotonin (5HT3A) receptors, of 5HT3-immunopositive interneurons caused an increase in amplitude and slowing of the delta rhythm until each period became the "wave" component of the spike and wave discharge. As with the normal delta rhythm, the wave of a spike and wave discharge originated in cortical layer 5. In contrast, the "spike" component of the spike and wave discharge originated from a relative failure of fast inhibition in layers 2/3-switching pyramidal cell action potential outputs from single, sparse spiking during delta rhythms to brief, intense burst spiking, phase-locked to the field spike. The mechanisms underlying this loss of superficial layer fast inhibition, and a concomitant increase in slow inhibition, appeared to be precipitated by a loss of neuropeptide Y (NPY)-mediated local circuit inhibition and a subsequent increase in vasoactive intestinal peptide (VIP)-mediated disinhibition. Blockade of NPY Y1 receptors was sufficient to generate spike and wave discharges, whereas blockade of VIP receptors almost completely abolished this form of epileptiform activity. These data suggest that aberrant, activity-dependent neuropeptide corelease can have catastrophic effects on neocortical dynamics.

Neuronal assembly dynamics in the beta1 frequency range permits short-term memory.

Cell assemblies have long been thought to be associated with brain rhythms, notably the gamma rhythm. Here, we use a computational model to show that the beta1 frequency band, as found in rat association cortex, has properties complementary to the gamma band for the creation and manipulation of cell assemblies. We focus on the ability of the beta1 rhythm to respond differently to familiar and novel stimuli, and to provide a framework for combining the two. Simulations predict that assemblies of superficial layer pyramidal cells can be maintained in the absence of continuing input or synaptic plasticity. Instead, the formation of these assemblies relies on the nesting of activity within a beta1 rhythm. In addition, cells receiving further input after assembly formation produce coexistent spiking activity, unlike the competitive spiking activity characteristic of assembly formation with gamma rhythms.

Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein.

The prion protein (PrP) is central to the aetiology of the prion diseases, transmissible neurodegenerative conditions of humans and animals. PrP null mice show abnormalities of synaptic neurophysiology, in particular weakened GABAA receptor-mediated fast inhibition and impaired long-term potentiation in the hippocampus. Here we demonstrate that this PrP null phenotype is rescued in mice with a high copy number of a transgene encoding human PrP but not in low copy number mice, confirming the specificity of the phenotype for loss of function of PrP. The ability of human PrP to compensate for loss of murine PrP will allow direct study of the functional consequences of the 18 human PrP mutations, which cause the inherited prion diseases; this phenotype can now form the basis of the first functional assay for PrP.

Detecting seizure origin using basic, multiscale population dynamic measures: preliminary findings.

Many types of electrographic seizures are readily identifiable by direct visual examination of electroencephalographic or electrocorticographic recordings. This process can, however, be painstakingly slow, and much effort has been expended to automate the process using various dynamic properties of epileptiform waveforms. As methods have become more subtle and powerful they have been used for seizure subclassification, seizure prediction, and seizure onset identification and localization. Here we concentrate on the last, with reference to seizures of neocortical origin. We briefly review some of the methods used and introduce preliminary results from a very simple dynamic model based on key electrophysiological properties found in some seizure types: occurrence of very fast oscillations (sometimes called ripples), excess gamma frequency oscillations, electroencephalographic/electrocorticographic flattening, and changes in global synchrony. We show how this multiscale analysis may reveal features unique to seizure onset and speculate on the underlying cellular and network phenomena responsible.

Impaired electrical signaling disrupts gamma frequency oscillations in connexin 36-deficient mice.

Neural processing occurs in parallel in distant cortical areas even for simple perceptual tasks. Associated cognitive binding is believed to occur through the interareal synchronization of rhythmic activity in the gamma (30-80 Hz) range. Such oscillations arise as an emergent property of the neuronal network and require conventional chemical neurotransmission. To test the potential role of gap junction-mediated electrical signaling in this network property, we generated mice lacking connexin 36, the major neuronal connexin. Here we show that the loss of this protein disrupts gamma frequency network oscillations in vitro but leaves high frequency (150 Hz) rhythms, which may involve gap junctions between principal cells (Schmitz et al., 2001), unaffected. Thus, specific connexins differentially deployed throughout cortical networks are likely to regulate different functional aspects of neuronal information processing in the mature brain.

Neuronal networks for induced '40 Hz' rhythms.

A fast, coherent EEG rhythm, called a gamma or a '40 Hz' rhythm, has been implicated both in higher brain functions, such as the 'binding' of features that are detected by sensory cortices into perceived objects, and in lower level processes, such as the phase coding of neuronal activity. Computer simulations of several parts of the brain suggest that gamma rhythms can be generated by pools of excitatory neurones, networks of inhibitory neurones, or networks of both excitatory and inhibitory neurones. The strongest experimental evidence for rhythm generators has been shown for: (1) neocortical and thalamic neurones that are intrinsic '40 Hz' oscillators, although synchrony still requires network mechanisms; and (2) hippocampal and neocortical networks of mutually inhibitory interneurones that generate collective 40 Hz rhythms when excited tonically.

Gamma-frequency oscillations: a neuronal population phenomenon, regulated by synaptic and intrinsic cellular processes, and inducing synaptic plasticity.

Neurons are extraordinarily complicated devices, in which physical and chemical processes are intercoupled, in spatially non-uniform manner, over distances of millimeters or more, and over time scales of < 1 msec up to the lifetime of the animal. The fact that neuronal populations generating most brain activities of interest are very large-perhaps many millions of cells-makes the task of analysis seem hopeless. Yet, during at least some population activities, neuronal networks oscillate synchronously. The emergence of such oscillations generates precise temporal relationship between neuronal inputs and outputs, thus rendering tractable the analysis of network function at a cellular level. We illustrate this idea with a review of recent data and a network model of synchronized gamma frequency (> 20 Hz) oscillations in vitro, and discuss how these and other oscillations may relate to recent data on back-propagating, action potentials, dendritic Ca2+ transients, long-term potentiation and GABAA receptor-mediated synaptic potentials.

Self-organized synaptic plasticity contributes to the shaping of gamma and beta oscillations in vitro.

gamma (30-70 Hz) followed by beta (10-30 Hz) oscillations are evoked in humans by sensory stimuli and may be involved in working memory. Phenomenologically similar gamma-->beta oscillations can be evoked in hippocampal slices by strong two-site tetanic stimulation. Weaker stimulation leads only to two-site synchronized gamma. In vitro oscillations have memory-like features: (1) EPSPs increase during gamma-->beta; (2) after a strong one-site stimulus, two-site stimulation produces desynchronized gamma; and (3) a single synchronized gamma-->beta epoch allows a subsequent weak stimulus to induce synchronized gamma-->beta. Features 2 and 3 last >50 min and so are unlikely to be caused by presynaptic effects. A previous model replicated the gamma-->beta transition when it was assumed that K(+) conductance(s) increases and there is an ad hoc increase in pyramidal EPSCs. Here, we have refined the model, so that both pyramidal-->pyramidal and pyramidal-->interneuron synapses are modifiable. This model, in a self-organized way, replicates the gamma-->beta transition, along with features 1 and 2 above. Feature 3 is replicated if learning rates, or the time course of K(+) current block, are graded with stimulus intensity. Synaptic plasticity allows simulated oscillations to synchronize between sites separated by axon conduction delays over 10 msec. Our data suggest that one function of gamma oscillations is to permit synaptic plasticity, which is then expressed in the form of beta oscillations. We propose that the period of gamma oscillations, approximately 25 msec, is "designed" to match the time course of [Ca(2+)](i) fluctuations in dendrites, thus facilitating learning.

Differential expression of synaptic and nonsynaptic mechanisms underlying stimulus-induced gamma oscillations in vitro.

Gamma frequency oscillations occur in hippocampus in vitro after brief tetani delivered to afferent pathways. Previous reports have characterized these oscillations as either (1) trains of GABA(A) inhibitory synaptic events mediated by depolarization of both pyramidal cells and interneurons at least in part mediated by metabotropic glutamate and acetylcholine receptors, or (2) field potential oscillations occurring in the near absence of an inhibitory synaptic oscillation when cells are driven by depolarizing GABA responses and local synchrony is produced by field effects. The aim of this study was to investigate factors involved in the differential expression of these synaptically and nonsynaptically gated oscillations. Field effects were undetectable in control recordings but manifested when slices were perfused with hypo-osmotic solutions or a reduced level of normal perfusate. These manipulations also reduced the amplitude of the train of inhibitory synaptic events associated with an oscillation and enhanced the depolarizing GABA component underlying the post-tetanic depolarization. The resulting field oscillation was still dependent, at least in part, on inhibitory synaptic transmission, but spatiotemporal aspects of the oscillation were severely disrupted. These changes were also accompanied by an increase in estimated [K(+)](o) compared with control. We suggest that nonsynaptic oscillations occur under conditions also associated with epileptiform activity and constitute a phenomenon that is distinct from synaptically gated oscillations. The latter remain a viable model for in vivo oscillations of cognitive relevance.

Gap junctions between interneuron dendrites can enhance synchrony of gamma oscillations in distributed networks.

Gamma-frequency (30-70 Hz) oscillations in populations of interneurons may be of functional relevance in the brain by virtue of their ability to induce synchronous firing in principal neurons. Such a role would require that neurons, 1 mm or more apart, be able to synchronize their activity, despite the presence of axonal conduction delays and of the limited axonal spread of many interneurons. We showed previously that interneuron doublet firing can help to synchronize gamma oscillations, provided that sufficiently many pyramidal neurons are active; we also suggested that gap junctions, between the axons of principal neurons, could contribute to the long-range synchrony of gamma oscillations induced in the hippocampus by carbachol in vitro. Here we consider interneuron network gamma: that is, gamma oscillations in pharmacologically isolated networks of tonically excited interneurons, with frequency gated by mutual GABA(A) receptor-mediated IPSPs. We provide simulation and electrophysiological evidence that interneuronal gap junctions (presumably dendritic) can enhance the synchrony of such gamma oscillations, in spatially extended interneuron networks. There appears to be a sharp threshold conductance, below which the interneuron dendritic gap junctions do not exert a synchronizing role.

Neuronal fast oscillations as a target site for psychoactive drugs.

Neuronal oscillations within the electroencephalogram beta and gamma bands (15-80 Hz) are associated with intense mental activity and cognitive function in general. Specifically, recent advances have implicated gamma oscillations in the processing of sensory stimuli and demonstrated that synchronous gamma oscillations, appearing concurrently in spatially separate brain regions, can induce beta activity. beta activity generated in this manner represents established synchronous communication between brain regions and is thought to represent a neuronal network correlate of the "binding phenomenon" in cognitive theory. This review will outline the mechanisms of generation of these oscillations at the cellular and network level, and will highlight the effects of drugs that may modify these mechanisms. Possible modification of fast oscillations by disease processes and clinical intervention are discussed.

The effects of general anaesthetics on carbachol-evoked gamma oscillations in the rat hippocampus in vitro.

The effects of general anaesthetics and temperature on carbachol-evoked gamma oscillations in the rat hippocampal brain slice preparation were investigated. The frequency of the oscillations was found to be dependent on temperature in the range 32-25 degrees C, with a linear reduction in frequency from 40-17 Hz over this temperature range. The volatile anaesthetics isoflurane and halothane, and the intravenous anaesthetics thiopental, propofol and R(+)-etomidate caused a reduction in the frequency of the oscillations, in a concentration-dependent manner, over a range of clinically relevant concentrations. On the other hand, the intravenous agent ketamine and the "inactive" S(-)-isomer of etomidate had no significant effect on the oscillation frequency. The oscillations were markedly asymmetric over one cycle with a relatively rapid "rising" phase followed by a slower "decaying" phase. The decrease in oscillation frequency was due to an increase in the time-course of the "decaying phase" of the oscillation with little effect on the "rising" phase, consistent with the idea that carbachol-evoked gamma oscillations are trains of GABAergic inhibitory postsynaptic potentials and that the anaesthetics are acting postsynaptically at the GABA(A) receptor.

Epileptic focus induced in rat by intrahippocampal cholera toxin: neuronal properties in vitro.

Injecting 0.5-1.0 microgram of cholera toxin into rat hippocampus induces a chronic epileptic focus which generates interictal discharges and brief epileptic seizures intermittently over the following seven to 10 days. Here we examined the electrophysiological properties of hippocampal slices prepared from these rats three to four days after injection, at the height of the epileptic syndrome. These slices generated epileptic discharges in response to electrical stimulation of afferent pathways. In many cases epileptic discharges occurred spontaneously in the CA3 subregion; these usually lasted < 200 ms, but they could last < 0.6 s. Intracellular recordings from pyramidal layer cells revealed depolarization shifts synchronous with the epileptic field potentials. These depolarization shifts had slow onsets compared with those induced by blocking inhibition with bicuculline (depolarizations started a mean of 57 ms before, and reached 5.2 mV by, the onset of the cholera toxin epileptic field potential, compared with 12 ms and 3.6 mV respectively for 70 microM bicuculline methiodide). Extracellular unit recordings showed that the slow predepolarization seen in the cholera toxin focus was associated with an acceleration of the firing of other pyramidal layer neurons. The epileptic activity in this model cannot be attributed to the loss of synaptic inhibition, because inhibitory postsynaptic potentials could be evoked when the synchronous bursts were blocked by increasing [Ca2+]o from 2 to 8 mM. Observations of monosynaptic inhibitory postsynaptic currents isolated by application of 20 microM 6-cyano-7-nitroquinoxaline-2,3-dione, 50 microM DL-2-amino-5-phosphonovaleric acid and 100-200 microM 3-amino-2-(4-chlorophenyl)-2-hydroxy-propylsulphonic acid showed a small effect of the toxin only on the time course of the inhibitory postsynaptic current. On the other hand, there were significant changes in the intrinsic properties of individual neurons. The membrane potentials of cells in the cholera toxin focus did not differ from those in slices from rats injected with vehicle solution, but their input resistances were significantly increased. Unlike the other cellular changes in this model, the increase in input resistance was not seen in slices exposed acutely to 1 micrograms/ml cholera toxin for 30 min, suggesting there may be morphological changes in the chronic focus. Action potential accommodation and the slow afterhyperpolarization were depressed in both acute and chronic epileptic tissue, indicating impairments of Ca(2+)- and/or voltage-dependent K+ currents, and we conclude that these provide the most likely basis for cholera toxin epileptogenesis.

Nitrendipine, given during drinking, decreases the electrophysiological changes in the isolated hippocampal slice, seen during ethanol withdrawal.

1. Extracellular recordings were made from mouse isolated hippocampal slices prepared after chronic treatment in vivo with either ethanol or ethanol plus the dihydropyridine calcium channel antagonist, nitrendipine. 2. The withdrawal of ethanol caused a variety of changes in the field potentials, as previously reported, including decreases in the thresholds for eliciting single and multiple population spikes, increases in paired pulse potentiation and shifts to the left of the input/output curves. 3. The addition of nitrendipine to the drinking mixture in the chronic ethanol treatment significantly decreased all the changes in the field potentials that were seen after ethanol withdrawal. 4. Addition of nitrendipine to the perfusion medium also decreased the signs of hyperexcitability seen in the hippocampal slices during ethanol withdrawal. 5. The results provide further evidence that neuronal calcium channels may be involved in ethanol dependence and that the adaptive changes caused by chronic ethanol treatment can be modulated by alterations at dihydropyridine-sensitive sites.

A calcium channel antagonist stereoselectively decreases ethanol withdrawal hyperexcitability but not that due to bicuculline, in hippocampal slices.

1. Extracellular recordings were made from CA1 area of isolated hippocampal slices of the mouse after chronic ethanol administration in vivo, with orthodromic stimulation of the Schaffer collateral/commissural fibres. 2. The (+)-isomer of the calcium channel antagonist PN 200-110 (isradipine) significantly decreased all the recorded signs of hyperexcitability in the slices during ethanol withdrawal. These included increased paired pulse potentiation and decreases in the thresholds for elicitation of single and multiple population spikes. 3. The (-)-isomer of PN 200-100 did not affect ethanol withdrawal hyperexcitability in the slices. 4. Neither isomer of PN 200-110 affected the field potentials in slices from control animals. 5. The gamma-aminobutyric acid (GABA) antagonist, bicuculline, lowered thresholds for eliciting population spikes in hippocampal slices from untreated animals. The active, (+)-isomer of PN 200-110 did not affect this action of bicuculline in hippocampal slices from untreated animals. 6. The stereoisomerism of the action of PN 200-110 on ethanol withdrawal hyperexcitability in the hippocampal slice was therefore the same as that seen in blockade of calcium channels. The results suggested that ethanol withdrawal hyperexcitability recorded in the isolated hippocampal slice involved increased activity of voltage-sensitive calcium channels.

Changes in intrinsic inhibition in isolated hippocampal slices during ethanol withdrawal; lack of correlation with withdrawal hyperexcitability.

1. Intracellular recordings were made from pyramidal cells in area CA1 in mouse isolated hippocampal slices, after chronic ethanol treatment in vivo. 2. Fast i.p.s.ps were isolated by injection of the impaled neurones with QX314 (to block fast sodium currents and the slow i.p.s.p.) and stimulating the interneurones in the presence of the glutamatergic blockers, CNQX and APV. 3. The isolated fast-inhibitory postsynaptic potential (f.-i.p.s.p.) was measured at intervals during the 7 h withdrawal period. The reversal potential and sensitivity to bicuculline suggested that the isolated f.-i.p.s.p. was mediated by activation of the GABAA receptor-chloride ionophore complex. 4. Measurement of stimulus-response relationships for the f.-i.p.s.ps revealed an initial increase in the maximum size of the i.p.s.p., evoked from a membrane potential of -50 mV, seen at 2 h into ethanol withdrawal. This was attributed to a negative shift in the reversal potential, Ei.p.s.p., with no observed change in conductance, Gi.p.s.p. 5. No differences in f.-i.p.s.ps evoked during ethanol withdrawal or in control slices were seen at 4 h or 6 h. At these times, epileptiform activity was seen in previous field potential recordings. 6. Paired pulse depression of the f.-i.p.s.p. was significantly increased at 2 h into withdrawal, when a 150 ms pulse interval was used. No differences were seen at later times in the ethanol withdrawal period. 7. The results suggest that ethanol withdrawal hyperexcitability in isolated hippocampal slices is not caused by primary decreases in inhibition mediated by the GABAA receptor-chloride ionophore complex.4. Measurement of stimulus-response relationships for the f.-i.p.s.ps revealed an initial increase in the maximum size of the i.p.s.p., evoked from a membrane potential of - 50 mV, seen at 2 h into ethanol withdrawal. This was attributed to a negative shift in the reversal potential, Ejp.sp with no observed change in conductance, Gj ps p.5. No differences in f.-i.p.s.ps evoked during ethanol withdrawal or in control slices were seen at 4 h or 6 h. At these times, epileptiform activity was seen in previous field potential recordings.6. Paired pulse depression of the f.-i.p.s.p. was significantly increased at 2 h into withdrawal, when a 150 ms pulse interval was used. No differences were seen at later times in the ethanol withdrawal period.7. The results suggest that ethanol withdrawal hyperexcitability in isolated hippocampal slices is not caused by primary decreases in inhibition mediated by the GABAA receptor-chloride ionophore complex.The increase in the f.-i.p.s.p. during the initial stages of the withdrawal might prevent the overt expression of epileptiform activity at this time.

Effects of intravenous anaesthetic agents on fast inhibitory oscillations in the rat hippocampus in vitro.

1. General anaesthetic agents prevent awareness of sensory input and subsequent recall of sensory events after administration. The mechanisms involved in higher sensory processing, including awareness and recall, are not fully elucidated. However, fast oscillations in neuronal activity in the 20-80 Hz (gamma) range have been strongly implicated. Here we have investigated the effects of two anaesthetic agents and a sedative/hypnotic drug on these oscillations. 2. Trains of fast oscillations, shown previously to be shaped by gamma-aminobutyric acid (GABAA) receptor activation, were evoked by pressure ejection of L-glutamate (10 nM) onto the perisomatic region of hippocampal area CAI in the presence of 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (R-CPP), 50 microM, 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX), 50 microM and 2-hydroxysaclofen, 0.2 mM. 3. Thiopentone (10-200 microM) and propofol (0.5-10 microM) dose-dependently decreased both the maximum oscillation frequency, by approx. 90%, and the incidence of evoked rhythmic oscillations by approx. 60%. Diazepam (0.05-1 microM) decreased maximum oscillation frequency by about 40% but did not affect the incidence of evoked oscillations. 4. The similar effects of thiopentone and propofol were mediated by both a large (about 600%) increase in the decay constant (tau D) of GABAA receptor-mediated inhibitory postsynaptic currents (i.p.s.cs) and a bicuculline-sensitive leak current. The two drugs had differing effects on i.p.s.c. amplitude. Diazepam caused a small increase in tau D (about 170%) and did not alter leak currents at the doses used. 5. Effects of the anaesthetic agents were seen on the above measurements at similar concentrations to those estimated in the CNS during clinical and veterinary anaesthesia. We suggest that the effects on fast oscillations associated with cognition may contribute to the mechanism by which these agents produce general anaesthesia.

Anaesthetic/amnesic agents disrupt beta frequency oscillations associated with potentiation of excitatory synaptic potentials in the rat hippocampal slice.

1. Anaesthetic agents produce disruption in cognitive function typified by reductions in sensory perception and memory formation. Oscillations within the EEG gamma and beta bands have been linked to sensory perception and memory and have been shown to be modified by anaesthetic agents. 2. Synchronous gamma oscillations generated by brief tetanic stimulation in two regions of hippocampal area CA1 in slices in vitro were seen to potentiate excitatory synaptic communication between the areas. This synaptic potentiation, was seen to contribute to a transition from gamma frequency (30 - 70 Hz) to beta frequency (12 - 30 Hz) oscillations. 3. Four drugs having anaesthetic/hypnotic and amnesic properties were tested on this synchronous gamma-induced beta oscillation. Thiopental 10 - 200 microM, Diazepam 0.05 - 1.0 microM, Morphine 10 - 200 microM, and Ketamine 10 - 200 microM were all added to the bathing medium. Each drug markedly disrupted the formation of beta oscillations in a manner consistent with their primary modes of action. Thiopental and morphine disrupted synchrony of gamma oscillations and prevented potentiation of recurrent excitatory potentials measured in stratum oriens (fEPSPs). Neither diazepam, nor ketamine produced such marked changes in synchrony at gamma frequencies or reduction in potentiation of fEPSPs. However, each disrupted expression of subsequent beta oscillation via changes in the magnitude of inhibitory network gamma oscillations and the duration and magnitude of tetanus-induced depolarization respectively. 4. The degree of disruption of fEPSP potentiation correlated quantitatively with the degree of disruption in synchrony between sites during gamma oscillations. The data indicate that synchronous gamma-induced beta oscillations represent a mode of expression of excitatory synaptic potentiation in the hippocampus, and that anaesthetic/amnesic agents can disrupt this process markedly.

Disruption of synchronous gamma oscillations in the rat hippocampal slice: a common mechanism of anaesthetic drug action.

1. At the molecular level much progress has been made towards elucidating the mechanisms of action of general and dissociative anaesthetics. However, little is known about how these molecular actions may lead to disruption of cognitive function. 2. A promising physiological correlate of cognitive function is the ability of spatially separate areas of the brain to synchronize firing patterns via mutual inhibitory, gamma-frequency (20-80 Hz) electrical oscillations. Here we examine the effects of five different anaesthetic/hypnotic agents with different primary mechanisms of action on these oscillations in the hippocampus. 3. Gamma oscillations were elicited simultaneously at two sites at either end of area CAI by tetanic stimulation. Such oscillations are synchronous between these areas even when separated by up to c. 4 mm in control conditions. 4. Agents which act directly on GABA(A) receptor-mediated inhibition had different effects on synchronous gamma oscillations. Thiopental (10-200 microm) markedly disrupted the oscillation and resulting synchrony whereas the benzodiazepines diazepam and temazepam (0.05-1.0 microM) had little effect. 5. The opiate morphine (10-200 microM) and dissociative agent ketamine (10-100 microM) had a different profile of effects on gamma oscillations. However, as with thiopental, both agents markedly disrupted between site synchrony. These three agents demonstrated this effect at aqueous concentrations relevant to anaesthetic ED50. 6. Using the hippocampus as a model neuronal network we propose that, despite differing primary mechanisms of action, anaesthetics may disrupt cognitive function by interfering with the mechanism of generation of synchronous firing patterns between spatially separate areas of the brain.